Abstract
Eosinophils are effector cells that have an important role in the pathogenesis of allergic disease. Defective removal of these cells likely leads to chronic inflammatory diseases such as asthma. Thus, there is great interest in understanding the mechanisms responsible for the elimination of eosinophils from inflammatory sites. Previous studies have demonstrated a role for certain mediators and molecular pathways responsible for the survival and death of leukocytes at sites of inflammation. Reactive oxygen species have been described as proinflammatory mediators but their role in the resolution phase of inflammation is poorly understood. The aim of this study was to investigate the effect of reactive oxygen species in the resolution of allergic inflammatory responses. An eosinophilic cell line (Eol-1) was treated with hydrogen peroxide and apoptosis was measured. Allergic inflammation was induced in ovalbumin sensitized and challenged mouse models and reactive oxygen species were administered at the peak of inflammatory cell infiltrate. Inflammatory cell numbers, cytokine and chemokine levels, mucus production, inflammatory cell apoptosis and peribronchiolar matrix deposition was quantified in the lungs. Resistance and elastance were measured at baseline and after aerosolized methacholine. Hydrogen peroxide accelerates resolution of airway inflammation by induction of caspase-dependent apoptosis of eosinophils and decrease remodeling, mucus deposition, inflammatory cytokine production and airway hyperreactivity. Moreover, the inhibition of reactive oxygen species production by apocynin or in gp91phox−/− mice prolonged the inflammatory response. Hydrogen peroxide induces Eol-1 apoptosis in vitro and enhances the resolution of inflammation and improves lung function in vivo by inducing caspase-dependent apoptosis of eosinophils.
Highlights
Apoptosis of leukocytes is regarded as an important process for the successful resolution of inflammatory responses
The results presented here can be summarized as follows: (i) treatment with H2O2 or strategies that enhanced H2O2 reduced eosinophil accumulation in the bronchoalveolar lavage (BAL) and lung tissue; (ii) H2O2 promoted resolution of inflammation by inducing caspasedependent apoptosis of eosinophils in vivo; (iii) H2O2 induced caspase-dependent apoptosis of a human eosinophilic cell line in vitro. (iv) H2O2 derived from NADPH oxidase was necessary for natural resolution of allergic inflammation; (v) treatment with H2O2 decreased secretion of mucus, Figure 3 H2O2 induces apoptosis of eosinophils
The superoxide dismutase (SOD) degrades O2− in H2O and produces H2O2.23 Our work is the first to describe the importance of the oxidative pathway involving NADPH oxidase to resolve eosinophilic response
Summary
Apoptosis of leukocytes is regarded as an important process for the successful resolution of inflammatory responses. Evidence for ROS-mediated anti-inflammatory actions has been described.[21] The importance for ROS production in the context of infection can be exemplified in patients with chronic granulomatous disease (CGD) where defective production in ROS results in multiple infections and often early death.[22,23] studies in mouse models have shown that NADPH oxidase is key for regulating lung inflammation and injury as well as NF-κB activation and downstream cytokine production in response to LPS.[24] More recently, our group has demonstrated that NADPH oxidase-derived H2O2 is directly linked to induction of apoptosis of neutrophils and resolution of inflammation in a model of antigen-induced arthritis.[18] the role of ROS in the context of the resolution of allergic inflammation is still unknown. Our study provides evidence that H2O2 is released during allergic inflammation in a gp91phox − / − -dependent manner and induces a caspase-dependent proapoptotic effect in eosinophils, having a crucial role in the resolution of allergic inflammation
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